Association of Cabozantinib Dose Reductions for Toxicity With Clinical Effectiveness in Metastatic Renal Cell Carcinoma (mRCC): Results From the Canadian Kidney Cancer Information System (CKCis)

Cabozantinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that has shown efficacy in the treatment of metastatic renal cell carcinoma (mRCC). In clinical practice, cabozantinib is typically administered orally once daily, with the standard starting dose being 60 mg. However, dose modifications, including dose reductions, may be necessary to manage treatment-related toxicities. As with other TKI’s, there is emerging data that suggests patients who require dose modifications for toxicity while on treatment with cabozantinib may have improved cancer outcomes.

In this study, we explored the association between cabozantinib dose reductions and treatment outcomes in patients with metastatic renal cell carcinoma (mRCC). Using data from the Canadian Kidney Cancer Information System (CKCis), encompassing 14 academic centers across Canada, we examined real-world treatment patterns and outcomes in 319 mRCC patients treated with cabozantinib between 2011 and 2021. Our findings offer insights into the potential impact of cabozantinib dose adjustments on patient outcomes in this clinical setting.

We observed that a considerable number of patients treated with cabozantinib required dose reductions during their treatment course, typically within the first 4 months of therapy initiation. Interestingly, patients who experienced these dose reductions demonstrated significantly improved overall survival (OS) and time to treatment failure (TTF) compared to those who did not require dose adjustments. This suggests a potential link between toxicity-driven dose modifications and treatment efficacy in mRCC.
While there was no discernible difference in the objective response rate (ORR) between patients with and without dose reductions, our findings suggest that the benefit associated with dose reductions may be more closely linked to prolonged disease control rather than increased response rates.

Interestingly, there was no significant association between the starting dose and response rate, OS, or TTF when comparing patients who started at 60 mg to those who started at a lower dose. This finding suggests that once patients are initiated on cabozantinib, the subsequent dose reductions for toxicity, rather than the starting dose itself, appear to be more predictive of treatment effectiveness.

Our study underscores the feasibility and potential benefits of toxicity-driven individualized dosing strategies, particularly with cabozantinib. By tailoring treatment regimens based on observed toxicity profiles, clinicians may optimize drug exposure and potentially improve treatment effectiveness and patient outcomes, while concurrently managing treatment related side-effects and maintaining quality of life. However, we acknowledge the limitations of our retrospective study design, including inherent biases, residual confounding factors, and immortal time bias. Therefore, further prospective validation with larger cohorts is needed to confirm these findings.

In summary, our study provides insights into the nuanced management of mRCC with cabozantinib, suggesting that toxicity-driven dose adjustments may serve as a surrogate marker for adequate drug exposure. These findings may have implications for clinical practice, potentially guiding the development of personalized dosing strategies to optimize outcomes in mRCC patients undergoing TKI therapy. Further prospective studies with larger sample sizes are warranted to validate these findings and explore the underlying mechanisms driving the association between TKI toxicity, dose reductions, and treatment outcomes in mRCC. Such studies could potentially inform treatment decision-making and guide individualized strategies for TKIs when given alone or in combination with immunotherapy.

Written by: Jeffrey Graham,¹ Sunita Ghosh,² Rodney H Breau,³ Lori Wood,⁴ Simon Tanguay,⁵ Dominick Bosse,⁶ Aly-Khan Lalani,⁷ Bimal Bhindi,⁸ Daniel Heng,⁹ Antonio Finelli,¹⁰ Nazanin Fallah-Rad,¹¹ Vincent Castonguay,¹² Naveen S Basappa,¹³ Denis Soulières,¹⁴ Frédéric Pouliot,¹⁵ Christian Kollmannsberger,¹⁶ Georg A Bjarnason¹⁷

CancerCare Manitoba, Division of Medical Oncology and Hematology, University of Manitoba, Winnipeg, MB, Canada.
Department of Medical Oncology, Faculty of Medicine and Dentistry University of Alberta, Edmonton, AB, Canada.
Division of Urology, University of Ottawa, Ottawa, ON, Canada.
Division of Medical Oncology, QEII Health Sciences Center, Halifax, NS, Canada.
Department of Surgery, McGill University, Montreal, QC, Canada.
Division of Medical Oncology, University of Ottawa, Ottawa, ON, Canada.
Division of Medical Oncology, McMaster University, Hamilton, ON, Canada.
Division of Urology, University of Calgary, Calgary, AB, Canada.
Division of Medical Oncology, University of Calgary, Calgary, AB, Canada.
Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Centre de recherche du Centre Hospitalier Universitaire de Québec - Université Laval (CRCHUQc-UL), Centre de recherche sur le cancer (CRC) de l'Université Laval, Québec, QC, Canada.
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada.
Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
Cancer Research Center, Centre Hospitalier Universitaire de Québec - Université Laval, Québec, QC, Canada.
BC Cancer - Vancouver Centre, Vancouver, BC, Canada.
Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

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